Summary: The branch is focusing on identifying the role of aberrant neutrophils and neutrophil extracellular traps in the development of autoimmune responses and end-organ damage in systemic diseases including lupus (SLE), rheumatoid arthritis (RA) and systemic vasculitides (AAV). During this year, our group has identified specific components of NETs that may be involved in inducing interferogenic responses in SLE. We are also studying how lupus neutrophils modulate T cell function and mechanisms of oxidant production by neutrophils that may promote immune-mediated damage in lupus and other diseases. Our work is also examining neutrophil/synovial fibroblasts interactions in the RA synovium and the role these play in triggering abnormal innate and adaptive immunity in this disease. During this year, we have reported that these interactions lead to the development of pathogenic RA-specific autoantibodies and cartilage damage in models of disease. Other areas of interest to our group pertaining to the role of neutrophils in autoimmunity relate to inflammatory myopathies and systemic vasculitis. Lupus patients have evidence of aberrant HDL, which is highly oxidized and displays abnormal function, as measured by reverse cholesterol transport. We have studied during this year how this HDL may modify myeloid cell function and promote inflammation leading to premature vascular disease. Following a bench to bedside approach we are actively studying a well-characterized cardiovascular lupus cohort, which is being followed prospectively for identification of novel biomarkers that predict progression of vascular inflammation, endothelial dysfunction and premature vascular events. We are using sophisticated imaging and functional vascular assays to quantify these abnormalities in lupus patients. We have an ongoing clinical trial to assess the role of PPAR-gamma agonists in modulating vascular function and disease activity in lupus patients, at the NIH Clinical Center. In collaboration with other investigators at NIAMS, we are investigating how JAK inhibitors may modulate autoimmunity and vascular damage in lupus in an ongoing clinical trial.